Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease-causing variants.

The Ashkenazi Jewish (AJ) population has an increased risk for a variety of recessive diseases due to historical founder effects and genetic drift. For some, the disease-causing founder mutations have been identified and well-characterized, but for others, further study is necessary. The purpose of this study is to assess the carrier frequencies of 85 pathogenic variants causative of 29 recessive conditions in the AJ population. Up to 3000 AJ individuals were genotyped by Luminex MagPlex® -TAG™ bead array or Agena Bioscience™ MassARRAY assays. We identified seven conditions with carrier frequencies higher than 1 in 100, nine between 1 in 100 and 1 in 200, and four between 1 in 200 and 1 in 500. Variants in nine conditions had a detected carrier rate of less than 1 in 500 or were not identified in approximately 2000 AJ individuals. We assessed the combined AJ carrier frequency for 18 relatively prevalent diseases to be 1 in 6, and the risk of AJ individuals to be a carrier couple for one of these 18 diseases as 1 in 441. We note additional recessive genetic conditions should be considered for AJ carrier screening panels.

Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.

A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria.

Scope and limitations of therapies: a neomillennial epistemological evaluation for helping medical practices.

Medical practice is in crisis - the sophistications are enormous and expensive, and the outcomes leave much to be desired. An epistemologic evaluation that weighs the scope and limitations of any -pathy or any procedure seems to be the need of the day. As an example, described herein is the logic of such an exercise; and a sample of the exercise itself, taking cancer as an example.

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.

PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

18F-FDG PET/CT helps in unmasking the great mimicker: A case of neurosarcoidosis with isolated involvement of the spinal cord. / La 18F-FDG PET/TC ayuda a desenmascarar a la gran imitadora: un caso de neurosarcoidosis con implicación aislada en la médula espinal.

A 36 year-old male with no significant past medical history presented with lower extremity numbness, gait instability, and urinary and bowel retention of 4 weeks onset. Spine MRI revealed diffuse oedema of cervicothoracic spinal cord with several solid enhancing intramedullary lesions, suggestive of metastases. The 18F-FDG PET/CT performed to identify the primary malignancy demonstrated mild hypermetabolic foci within the cervicothoracic cord, as well as a mildly hypermetabolic bilateral hilar lymphadenopathy and a mildly hypermetabolic pulmonary nodule, suggestive of sarcoidosis versus metastasis. The diagnosis of sarcoidosis was supported by identifying non-caseating granuloma in the biopsy of the pulmonary nodule. The patient responded well to steroid-therapy, with the symptoms being resolved within 3 weeks.

Recognition and management of acute kidney injury in children: The ISN 0by25 Global Snapshot study.

BACKGROUND: In low and middle-income countries, reliable data on the epidemiology of childhood acute kidney injury (AKI) is lacking. The Global Snapshot, conducted by the ISN "0by25" AKI initiative, was a world-wide cross-sectional, observational study to evaluate AKI in hospitalized patients. Here we report the pediatric results of this study. PATIENTS AND METHODS: We prospectively collected data on children who met the Kidney Disease Improving Global Outcomes AKI criteria during a 10-week window in late 2014. AKI risk factors, etiological factors, management and outcomes were recorded using standardized forms and protocols. Countries were classified according to their 2014 gross national income (GNI) per person into high-income countries (HIC), upper-middle income countries (UMIC) and low and low-middle income countries (LLMIC). Need for renal replacement therapy, mortality, and renal recovery were assessed 7 days after AKI diagnosis or at hospital discharge, whichever came first. RESULTS: 92 centers from 41 countries collected data on 354 pediatric AKI patients; 53% of the children developed AKI while hospitalized and 47% in the community. The most common etiological factors for AKI differed across GNI categories as well as between patients with community-acquired vs. hospital-acquired AKI. Children from HIC were younger, and larger proportion of AKI in this group were due to post-surgical complications vs. other etiologies when compared to other income categories. In patients with hypotension as the cause of AKI, the adjusted risk of death was almost 10-fold higher compared to patients without hypotension as an etiological factor for AKI development. Mortality was similar within AKI stages in HIC and UMIC. In LLMIC, patients with the highest AKI level of severity had higher mortality than patients in higher income categories. Patients from LLMIC and UMIC had a 57-fold and 11 fold higher adjusted risk of death, respectively, compared to patients from HIC. CONCLUSION: In resource-limited countries, pediatric AKI-associated mortality is disproportionately higher when compared to high-resource areas, especially among patients with more severe AKI.

Renal cell carcinoma with X;1 translocation in a child with Klinefelter syndrome.

Klinefelter syndrome (KS) is a sex chromosome abnormality occurring in 1 in 1,000 males. An association with leukemia, germ cell tumor, and male breast cancer has been suggested in KS. Such information is important for professionals caring for KS patients as the condition is frequently not clinically recognizable until after puberty. We report on a renal cell carcinoma (RCC) in a 10-year-old boy with KS. He developed intermittent hematuria at age 10 years and was diagnosed with a right kidney mass, which on pathology was identified as RCC. In addition, he was known to have learning disabilities and language delays. Analysis of peripheral blood chromosomes showed a 47,XXY karyotype while analysis of tumor cells demonstrated clonal abnormalities including a translocation between chromosomes X and 1, designated 47,XXYc,t(X;1)(p11.2;q21)[6]/47,XXYc,t(X;1),r(Xp)[2]/46,X XYc,-X,t(X;1)[7]. Renal cell carcinoma is rare in childhood and is not previously reported in KS. The oncogenetic significance of the chromosomal regions involved in this translocation is discussed in relation to the congenital abnormality of the patient.

Lateral nasal proboscis: antenatal diagnosis and counseling.

BACKGROUND: Lateral nasal proboscis is a rare anomaly resulting in incomplete formation of one side of the nose and other variable abnormalities in the adjoining regions of the face, without associated brain malformations. We report a case diagnosed antenatally and confirmed after birth of the infant. CASE: A 32-year-old white gravida 2 para 1 was referred for a comprehensive fetal ultrasound at 30.5 weeks to evaluate a facial anomaly seen on an ultrasound done to evaluate decreased fetal movements. A fingerlike projection was seen in the left inner eye area with visualization of one nostril and a small nose. After a spontaneous delivery at term, a 3845-g healthy female infant with lateral nasal proboscis and other locally associated anomalies was born and is doing well at 9 months. Reconstructive surgery was done at 3 and 6 months. CONCLUSION: Accurate antenatal diagnosis of lateral nasal proboscis is possible with ultrasound, which is important because its prognosis and management are different from other types of proboscides.

Recurrence risks for common complications of pregnancy--a review.

A review of the literature concerning the more common complications of pregnancy indicates that recurrence risks are available for most and can be summarized as follows: hydatidiform mole--1.3 to 2.9 per cent; recurrent miscarriage--20 to 30 per cent; ectopic pregnancy--20 to 30 per cent; severe preeclampsia--7.5 per cent; mild preeclampsia--29 per cent; preterm labor--15 per cent after one and 30 per cent after two. While recognizing that each individual case merits full investigation and careful assessment, it is proposed that these risk figures provide a useful basis for use in pre- and postpregnancy counseling.

Radio-active iodine uptake in vitiligo.

Vitiligo and thyroid disease are commonly associated disorders. Twenty-two clinically euthyroid vitiligo patients were studied for functional assessment of thyroid by radioactive iodine uptake assay. Half of them showed abnormal uptake values at 24 hours. Of these patients, 90% had lower values indicating a tendency towards developing hypothyroid state. Subclinical thyroid dysfunction in vitiligo appears to be an adaptive change.

Ear-lobe crease and ear-canal hair as predictors of coronary artery disease in Indian population.

215 patients of different communities were selected randomly to predict the correlation between the ear-lobe crease, ear-canal hair and coronary artery disease. On analysis, it was found that prevalence of the ear-lobe crease increases with advancing age, and the incidence was much more higher in Sindhis in whom the overall incidence of CAD is also significantly high. Bilateral diagonal ear-lobe crease was found to be significantly (P less than 0.001) associated in patients with documented CAD, and a significant difference was also observed between men with and without CAD in the presence of ear-canal hair with age matched group. The combined presence of ear-lobe crease and ear-canal hair was more definite and more sensitive index of underlying CAD.

Aluminium phosphide poisoning. Two cases with rare presentation.

We report two cases of aluminium phosphide poisoning who presented with rare manifestations, one with bleeding diathesis, hepatitis and acute tubular necrosis and the other with acute respiratory failure.

Jaccoud's arthritis.

A 16 year old girl with multivalvular heart disease and recurrent episodes of polyarthritis with correctable deformities of hands and feet fitting into that of Jaccoud's arthritis is reported. The condition is rare and often difficult to differentiate from rheumatoid arthritis.

Adult respiratory distress syndrome following aluminium phosphide ingestion. Report of 4 cases.

Four cases of adult respiratory distress syndrome (ARDS) following aluminium phosphide ingestion (ALP) are being reported. The dose of the intoxicant varied from 2 tablets (6.0 gm) to 3 tablets (9.0 gm). All patients had shock at admission and developed ARDS within 6 hours. The exhalation of Phosphine, (PH3) detected by positive silver nitrate paper test, was the possible noxious triggering factor in our cases. The cases are being reported because of their rare occurrence.

Plasma renin activity in shock due to aluminium phosphide poisoning.

Plasma renin activity (PRA) was estimated in 30 patients with aluminium phosphide (AIP) poisoning (study group) admitted in shock. Ten patients in shock other than due to AIP poisoning (Group II A) and 20 normal healthy subjects (Group II B) served as controls. The PRA was significantly higher in the study group and group II A as compared to normal healthy subjects (p less than 0.001). Significantly higher PRA was found in the study group as compared to Group II A (p less than 0.001). The initial higher PRA continued to rise further in the study group but it started decreasing in Group II A as the duration of shock advanced. Continuation of shock in AIP poisoning was probably due to slow release of toxic PH3 gas, which was detected by positive silver nitrate paper test. The rise in PRA was directly proportional to the dose of pesticide consumed. There was direct relationship of mortality with increased PRA. Angiotensin converting enzyme inhibitors may have a role in combating shock in AIp poisoning.

Reaction of peripheral nerves to vascular and bacterial injuries.

Mouse sciatic nerves were subjected to devascularization, M. leprae inoculation, and combined insult of devascularization + footpad inoculation (FPI). Changes were seen in FPI nerves only after eight months, but in cases of combined insult, changes were evident in hours. Both the groups showed initial loss of small myelinated fibres. No proliferation of Schwann cells was in FPI nerves, but in combined insult it was maximum after two weeks. Presence of M. leprae seems to be arresting Schwann cell activity after two weeks. Blood vessels showed increased endothelial cell cytoplasm, basement membrane proliferation and villi formation. These changes seem to be specific of endoneurial blood vessels of leprosy nerves. Increased number of mast cells seems to be specific of devascularized and FPI nerves. Increased number of macrophages expressed low immunity of devascularized nerves. Eosinophils migrated to endoneurium as a result of leakage of axoplasm.

Ultrastructure of sciatic nerve of armadillo infected with Mycobacterium leprae.

Ultrastructural observation of sciatic nerves from eight Armadillos were made. Six animals had intravenous inoculation of M. leprae, one had of foot pad, while one had natural leprosy. The available nerves were biopsied at various time sequence ranging from five weeks to twenty four months. Semithin sections did not reveal any neuropathy. Ultrastructurally perineurium was thick and endoneurial collagen was increased. Initially demyelination of non-myelinated fibres was seen in all nerves irrespective of mode of infection. This was followed by demyelination of small myelinated fibres. Active remyelination was predominantly after 17 months. Schwann cell activity was increased and various stages of division were seen. Bacilli were extracellular, intraxonal, in endothelium and in perineurium. Significant observations were on blood vessels. These observations are discussed.

Alkaline phosphatase activity in peripheral nerves and endothelial cell cultures in leprosy.

Alkaline phosphatase activity in leprosy nerves was studied. The activity was mainly in blood vessels and was maximum in healthy nerves. Low levels were seen in crush injury. In leprosy lower levels were in BT than LL cases. Endothelial cells (in vitro) released alkpase when infected with live bacilli only. No response was observed with heat killed bacilli.